ACTH antagonists
Open accessAbstract
Structural modifications within the active site of the ACTH molecule have produced analogs that inhibit the hormone sensitive adenylate cyclase system of bovine adrenal cortical plasma membranes. It is demonstrated that the tryptophan residue of the ACTH molecule is essential for stimulation of the enzyme. Substitution of tryptophan by phenylalanine or by N(alpha)-methyltryptophan as in [Gln(5), Phe(9)]corticotropin(1-20) amide or [N(alpha)-Metrp(9)]corticotropin(1-24) provides ACTH analogs that exhibit high affinity for the ACTH receptor(s) but fail to activate the adenylate cyclase system. It is concluded that affinity for the receptors alone is not sufficient for expression of hormonal activity. The observation that adrenal cortical adenylate cyclase activated by fluoride ion is not inhibited by the antagonists indicates that hormonal and fluoride activation proceed via different mechanisms.
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Hoffman developed an ACTH analog in which the Trp residue at position 9 of the HFRW message sequence was substituted with Phe or N-methyl Trp, and showed inhibition of ACTH-stimulated cAMP generation on bovine adrenal membranes.
“Hoffman therefore used a different approach and developed an analog in which the Trp residue at position 9 of the HFRW message sequence was substituted with Phe or N-methyl Trp, and showed inhibition of ACTH stimulated cAMP generation on bovine adrenal membranes (55).”
From ACTH Antagonists (2016) · cites this paper as [55]
The Results and Discussion (page unavailable) report that both Trp9-substituted analogs inhibited ACTH-stimulated adenylate cyclase in bovine adrenal cortical membranes; the Methods state that cAMP was measured. The Methods also say the Phe9 analog was prepared in the authors’ laboratories, but the N-methyl-Trp analog was a gift from Dr. W. Rittel, so attributing development of both analogs to Hofmann overstates the source. (LLM, conf=0.88)
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Cites
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ON THE ENZYMIC ACTIVITY OF SUBTILISIN-MODIFIED RIBONUCLEASE
Richards, F. M. (1958) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.44.2.162 · Cited by 234 · see citing works
Rodbell, M., Birnbaumer, L., Pohl, S. L., & Sundby, F. (1971) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.68.5.909 · Cited by 133 · see citing works
Hofmann, K. H., Wingender, W., & Finn, F. M. (1970) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.67.2.829 · Cited by 85 · see citing works
Self-citationSchwyzer, R., Schiller, P. W., SEELIG, S. A., & Sayers, G. (1971) · FEBS Letters · doi:10.1016/0014-5793(71)80520-3 · Cited by 80 · see citing works
Chemistry and function of polypeptide hormones
Hofmann, K. (1962) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.31.070162.001241 · Cited by 69 · see citing works
Self-citationLocalization of an Adrenocorticotropic Hormone Receptor on Bovine Adrenal Cortical Membranes
Finn, F. M., Widnell, C. C., & Hofmann, K. H. (1972) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)44815-1 · Cited by 68 · see citing works
Self-citationSeelig, S., Sayers, G., Schwyzer, R., & Schiller, P. (1971) · FEBS Letters · doi:10.1016/0014-5793(71)80521-5 · Cited by 68 · see citing works
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Self-citationPolypeptides. XLVI. Synthesis of a stably labeled, biologically active adrenocorticotropin fragment
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Self-citation
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Research works printed but not linked: 6
- [1]Richards, F. M. (1958) Proc. Nat. Acad. Sci. USA 44, 162– 166.
- [3]For a review see Finn, F. M. & Hofmann, K. (1973) Accounts Chem. Res. 6, 169-176.
- [4]For a review see Westheimer, F. H. (1962) Advan. Enzymol. 24,441–482.
- [14]Fujino, M., Hatanaka, C., Nishimura, O., Nakayama, R., Shitaka, M. & Fujiwara, R. (1971) Proc. 8th Symp. Pept. Chem., Osakà, 101–105.
- [16]Hofmann, K., Wingender, W. & Finn, F. M. (1970) Proc. Nat. Acad. Sci. USA 67, 829–836.
- [23]Rodbell, M., Birnbaumer, L., Pohl, S. L. & Sundby, F. (1971) Proc. Nat. Acad. Sci. USA 68, 909–913.
Cited by
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Clark, A. J., Forfar, R., Hussain, M., Jerman, J., McIver, E., Taylor, D., & Chan, L. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00101 · Cited by 49 · see citing works
“” Hoffman therefore used a different approach and developed an analog in which the Trp residue at position 9 of the HFRW message sequence was substituted with Phe or N -methyl Trp, and showed inhibition of ACTH stimulated cAMP generation on bovine adrenal membranes (55).”
BackgroundDevelopment of potent selective competitive-antagonists of the melanocortin type 2 receptor
Bouw, E., Huisman, M., Neggers, S. J. C. M. M., Themmen, A. P. N., van der Lely, A. J., & Delhanty, P. J. D. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.07.003 · Cited by 22 · see citing works
- Authors
- Hofmann, K., Montibeller, J. A., & Finn, F. M.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1974-01
- Volume
- 71
- Issue
- 1
- Pages
- 80-83
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC387936
- OpenAlex
- W2578183842
- Cited by
- 33
- References
- 19
- Citations by year
- 2020: 1 · 2016: 2 · 2014: 3 · 2013: 1
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- ACTH analogs, tryptophan, tryptophan substitution, adenylate cyclase inhibition, adrenal cortex, ACTH receptor, fluoride activation, structure-activity relationship
- MeSH terms
- Cyclic AMP, Adenylyl Cyclases, Adrenal Glands, Adrenocorticotropic Hormone, Amino Acid Sequence, Animals, Binding Sites, Cattle, Cell Membrane, Enzyme Activation, Fluorides, Receptors, Cell Surface, Stimulation, Chemical, Structure-Activity Relationship, In Vitro Techniques
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